WO2005102381A1 - Agent densifiant les os caracterise en ce qu'il utilise un inhibiteur de cathepsine k avec une pth - Google Patents

Agent densifiant les os caracterise en ce qu'il utilise un inhibiteur de cathepsine k avec une pth Download PDF

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WO2005102381A1
WO2005102381A1 PCT/JP2005/007767 JP2005007767W WO2005102381A1 WO 2005102381 A1 WO2005102381 A1 WO 2005102381A1 JP 2005007767 W JP2005007767 W JP 2005007767W WO 2005102381 A1 WO2005102381 A1 WO 2005102381A1
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alkyl
cyca
bone
hydrogen atom
formula
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PCT/JP2005/007767
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Japanese (ja)
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Yasuo Ochi
Makoto Tanaka
Naoki Kawada
Hiroyuki Yamada
Hiroshi Mori
Ryouji Kayasuga
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Ono Pharmaceutical Co., Ltd.
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Priority to US11/587,557 priority Critical patent/US7632813B2/en
Priority to JP2006512615A priority patent/JPWO2005102381A1/ja
Priority to EP05734608A priority patent/EP1741441A4/fr
Publication of WO2005102381A1 publication Critical patent/WO2005102381A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a bone mineral density increasing agent containing a cathepsin K inhibitor and PTHs as active ingredients.
  • the present invention relates to a therapeutic and / or prophylactic agent for bone metabolic disease comprising a cathepsin K inhibitor and PTHs as active ingredients.
  • Cathepsin K is a type of cysteine protease and belongs to the papain superfamily. Cathepsin K is specifically recognized in osteoclasts and has the activity of degrading bone matrix [J. Biol. Chem., 271, 12517 (1996)]. For bone metabolic disorders such as osteoporosis, fracture, arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia, carcinoma bone metastasis, periodontal disease, bone page et al disease with pathological bone resorption It is expected to show the effect.
  • PTH also referred to as parathyroid hormone, paratolmon or parathyroid hormone
  • parathyroid hormone is considered to be produced by chief cells of the parathyroid gland, and is a hormone that causes blood calcium. It has the characteristic that the concentration is increased but controlled by the phosphorus concentration.
  • PTH exhibits an osteogenesis promoting effect by intermittent administration and increases bone density.
  • PTH is expected to be a new therapeutic agent for osteoporosis because bone resorption inhibitors have an osteogenesis-promoting action unlike existing drugs that are mainly used.
  • Osteoporosis is classified into two types of pathology, primary osteoporosis and secondary osteoporosis.
  • Primary osteoporosis mainly includes postmenopausal osteoporosis, senile osteoporosis and the like.
  • Secondary osteoporosis mainly includes diabetic osteoporosis, steroid osteoporosis and the like.
  • Postmenopausal osteoporosis and senile osteoporosis also exhibit a condition in which bone rotation is abnormal due to imbalance between bone resorption and bone formation. Therefore, bone resorption inhibitors and osteogenesis promoters are effective in treating osteoporosis and should be used in combination. Thus, it is considered that the balance of bone rotation can be improved.
  • BP bisphosphonate
  • calcium preparations calcium preparations
  • estrogen receptor modulators androgen receptor modulators
  • calcitonin preparations a calcitonin gene-related peptide preparations
  • Ibriflavone preparations anabolic steroid preparations
  • anti-RANKL receptor activator of NF-kappa B ligand
  • bone formation promoters include PTHs, PTHrP (parathyroid hormone-related protein), BMP (bone morphogenetic protein), prostaglandin receptor agonist (EP agonist, EP agonist
  • CaR calcium sensing receptor
  • GSK glycosyl kinase
  • vitamin D and its derivatives, vitamin K and its derivatives, strontium preparations, HMG-CoA reductase inhibitors, steroids, caspase-1 inhibitors, prostaglandin receptor antagonists, and pharmacologic X receptor agonists Drugs, progesterone agonists, anti-TNF- ⁇ antibodies, anti-IL-6 antibodies, female hormone preparations, anti-inflammatory drugs, meta-oral protease inhibitors and the like are also used as therapeutic and / or prophylactic agents for bone metabolic diseases.
  • BP used for the treatment of osteoporosis has the effect of inhibiting bone resorption. It is considered that BP inhibits bone formation (Osteoporosis Japan, 7 (2), 11-16, 1999, Bone, 23 (4), 333-342, 1998).
  • Bone metabolic diseases are chronic diseases, and their treatment is often long-term. Therefore, combinations of multiple drugs are being considered to increase patient compliance and therapeutic efficacy.
  • an osteogenesis promoter and a bone resorption inhibitor are expected to further increase the bone density, but alendronate sodium hydrate (a BP product), a type of bone resorption inhibitor, is expected.
  • alendronate sodium hydrate a BP product
  • a type of bone resorption inhibitor is expected.
  • a cathepsin K inhibitor As a drug having a bone resorption inhibitory action, a cathepsin K inhibitor is known. It has been reported that, unlike BP, a cathepsin K inhibitor does not suppress bone formation in monkeys ( Non-Patent Document 3).
  • cathepsin K inhibitors and other drugs BP, estrogen receptor modulator, androgen receptor modulator, PTH, PTHrP, osteoclast proton ATPase inhibitor, HMG-CoA reduction Enzyme inhibitor, ⁇ receptor antagonist, ⁇ 38 kinase inhibitor
  • Drug growth hormone, ⁇ agonist, TNF- ⁇ inhibitor, ⁇ 2 ⁇ 7 receptor agonist, matrix meta
  • a combination preparation containing an oral proteinase inhibitor, a VEGF inhibitor, etc. is useful for diseases of osteoporosis, osteoarthritis, and tumor metastasis (see Patent Document 1).
  • Patent Document 1 International Publication No. 03Z039534 pamphlet
  • Patent Document 2 International Publication No. 03Z091202 pamphlet
  • Non-Patent Document 1 The 'New England' Journal 'of' Medicine, 2003, Vol. 349, No. 13, 1207-1215
  • Non-Patent Document 2 The 'New England' Journal 'of' Medicine, 2003, Vol. 349, No. 13, 1216-1226
  • Non-Patent Document 3 Journal 'Ob' Bone 'and' Mineral 'Research, 2001, Vol. 16, No. 10, 1739—1746
  • a cathepsin K inhibitor which is a bone absorption inhibitor, in particular, a compound represented by the following general formula (W):
  • W a compound represented by the following general formula (W):
  • the present invention relates to a bone density increasing agent comprising a combination of a cathepsin K inhibitor and one or more PTHs.
  • the present invention provides a method for treating osteoporosis, fracture, arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia, carcinoma bone metastasis, periodontal disease, comprising a combination of a cathepsin K inhibitor and one or more PTHs. And a therapeutic and / or prophylactic agent for bone metabolic diseases such as bone Page-et disease.
  • the present invention provides
  • a bone mineral density increasing agent comprising a combination of a cathepsin K inhibitor and PTHs
  • Cathepsin K inhibitor has the general formula (W)
  • R is (1) hydrogen atom, (2) CycA, (3) halogen atom, CycA, nitro, trifluoromethyl and cyano force. 8 alkyl, [0028]
  • CycA is a C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring, or 1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1-2 A 3- to 15-membered monocyclic, bicyclic or tricyclic heterocyclic ring containing a sulfur atom of
  • R 16 represents (1) C1-8 alkyl, (2) C2-87 alkyl, (3) C2-8 alkyl, (4) CycA, or (5) halogen atom, nitro, trifluoromethyl , ShiaIri CycA, - NR 18 R 19, - oR 18, - SR 18, - NHC (O) - CycA and - NHC (0) 0- (Cl ⁇ 8 alkyl) or al 1-5 selected Represents Cl-8 alkyl, C2-87 alkyl, or C2-8 alkyl substituted by a group;
  • R 17 , R 18 and R 19 each independently represent a hydrogen atom, Cl-4 alkyl, CycA, or Cl-4 alkyl substituted by CycA.
  • AA 1 is (1) a single bond, or
  • R 1 and R 2 each independently represent (0 hydrogen atom, (ii) Cl-8 alkyl, (iii) Cy cA, or (iv) the following (a) to (j) ):
  • R 1 and R 2 together form a C 2-8 alkylene (one of the carbon atoms in the alkylene chain is It may be replaced by an oxygen atom, a sulfur atom, or —NR 2 ° —, and the alkylene may be substituted by —NR 21 R 22 , —OR 23 , or oxo. )
  • R 2 ° represents a hydrogen atom, Cl-4 alkyl, — (0) 0 (J 1-4 alkyl), J.8, or Cl-4 alkyl substituted by CycA;
  • R 21 , R 22 , R 23 and R 25 each independently represent a hydrogen atom, Cl-4 alkyl, Cyc A, or CI-4 alkyl substituted by CycA,
  • R 24 represents Cl-4 anolequinole, CycA, —NR 21 R 22 , —OR 23 , —SR 23 , or Cl-4 alkyl substituted by CycA. ),
  • R 3 is a hydrogen atom, Cl-8 alkyl, CycA, or a force representing Cl-8 alkyl substituted by CycA, or
  • R 3 is, together with R 1 , a C 2-6 alkylene (one of the carbon atoms in the alkylene chain is an oxygen atom, a sulfur atom or —NR 2G —the alkylene is —NR 2 1 R 22 , -OR 23 , or one SR 23 , or oxo.). ) Or
  • CycB represents a 5- to 12-membered monocyclic or bicyclic heterocyclic ring, and other symbols represent the same meaning as described above.
  • AA 2 comprises (1) a single bond
  • R 4 and R 5 each independently represent (0 hydrogen atom, (ii) Cl-8 alkyl, (iii) Cy cA, or (iv) the following (a) to (j):
  • R 4 and R 5 together form a C 2-8 alkylene (one of the carbon atoms in the alkylene chain may be replaced by an oxygen atom, a sulfur atom, or —NR 3G —, and the alkylene is —NR 31 R 32 , -OR 33 , -SR 33 , or oxo.)
  • R 3 ° represents a hydrogen atom, Cl-4 alkyl, 44alkyl), ⁇ , or Cl ⁇ alkyl substituted by CycA,
  • R 31 , R 32 , R 33 and R 35 each independently represent a hydrogen atom, Cl-4 alkyl, Cyc A, or CI-4 alkyl substituted by CycA,
  • R 34 represents Cl-4 alkyl, CycA, —NR 31 R 32 , —OR 33 , —SR 33 , or Cl-4 alkyl substituted by CycA. ),
  • R 6 is a hydrogen atom, Cl-8 alkyl, CycA, or a force representing Cl-8 alkyl substituted by CycA, or
  • R 6 is taken together with R 4 or R to form a C 2-6 alkylene (where one of the carbon atoms in the alkylene chain is replaced by an oxygen atom, a sulfur atom, or —NR 3 — NR 31 R 32 , OR 33 , SR 33 , or oxo.)
  • R 38 is a hydrogen atom, Cl-4 alkyl, CycA, or a force representing C 1-4 alkyl substituted by CycA, or when AA 1 is a single bond, R 38 is taken together with R to form C 2-6 alkylene (one oxygen atom of the carbon atoms in the alkylene chain, a sulfur atom or NR 37 - (in group, R 37 is ⁇ it may also be replaced by representing) a hydrogen atom or a Cl ⁇ 4 alkyl..) represents the ,
  • CycC represents a 3 to 17 membered monocyclic or bicyclic heterocyclic ring
  • CycD represents a C3-14 monocyclic or bicyclic carbocyclic ring, or a 3-14 membered monocyclic or bicyclic heterocyclic ring.
  • AA 2 is connected with AA 1 , [0036] [I-Dori 7]
  • CycE represents a 4- to 18-membered monocyclic or bicyclic heterocyclic ring
  • CycF represents a 5- to 8-membered monocyclic heterocyclic ring
  • R 7 and R 8 are each independently (1) a hydrogen atom, (2) C1-8 alkyl, (3) CycA, or (4) the following (i) to (x) ):
  • a force which is also selected is a force representing Cl-8 alkyl substituted by 1 to 5 groups, or
  • R 7 and R 8 together form a C 2-8 alkylene (one of the carbon atoms in the alkylene chain may be replaced by an oxygen atom, a sulfur atom, or —NR 4G —, and the alkylene is —NR 41 R 42 , -OR 43 , — SR 43 , or oxo.)
  • R 4 ° represents a hydrogen atom, Cl-4 alkyl, ⁇ (0) 0 (114 alkyl), ⁇ . 8, or Cl-4 alkyl substituted by CycA,
  • R 41 , R 42 , R 43 and R 45 each independently represent a hydrogen atom, Cl-4 alkyl, Cyc A, or CI-4 alkyl substituted by CycA,
  • R 44 represents Cl-4 alkyl, CycA, — NR 41 R 42 , —OR 43 , — SR 43 , or Cl-4 alkyl substituted by CycA;
  • R 46 and R 47 each independently represent a hydrogen atom or Cl-8 alkyl
  • R 9 is hydrogen, Cl-8 alkyl, CycA, or a force representing Cl-8 alkyl substituted by CycA, or
  • R 9 is taken together with R 7 or R to form a C 2-6 alkylene (where one of the carbon atoms in the alkylene chain may be replaced by an oxygen atom, a sulfur atom, or —NR 4 — one NR "R 42, -OR 43, - SR 43, or may be substituted by Okiso). (In the group, all symbols have the same meanings as described above.)
  • [0039] represents a group represented by the following (1), (2) or (3):
  • R A1 and R A2 each independently represent (0 hydrogen atom, (ii) Cl-8 alkyl, (iii) C2-87 alkyl, (iv) —NR zl R z2 , (V) — OR z3 , (vi) — SR z3 , (vii) — COR z4 , (viii) Cy cP, or (ix) CycP, one NR Z1 R Z2 , -OR 23 , — SR Z3 , one COR z4 , one SO R z4 , one CO
  • R Z1 and R Z2 each independently represent a hydrogen atom, Cl-8 alkyl, C2-87 alkyl, CycP, C2-8 acyl, or CycP, C2-8 acyl, Cl-8 alkoxy Cl-8alkyl substituted by C1-8alkylthio, C1-8monoalkylamino or di (C1-8alkyl) amino,
  • R Z3 is a hydrogen atom, Cl-8 alkyl, C2-87 alkyl, CycP, or CycP, C1-8 alkoxy, Cl-8 alkylthio, amine-containing Cl-8 monoalkylamino-containing di (Cl-8 alkyl) Amino and C2-8 alkoxy represent Cl-8 alkyl substituted by 1 to 5 groups selected,
  • R Z4 is Cl-8 alkyl, CycP, or CycP, Cl-8 alkoxy, Cl-8 alkylthio, mono (Cl-8 alkyl) amidi-containing di (Cl-8 alkyl) amino and C2-8 alkyl. Represents a Cl-8 alkyl substituted by 1 to 5 groups;
  • R Z5 and R Z6 each independently represent a hydrogen atom or Cl-8 alkyl
  • CycP is a C4-10 carbocycle, or 1-4 nitrogen atoms, 1-2 oxygen atoms and Z represents a 5- to 10-membered heterocyclic ring containing 1-2 sulfur atoms, R 1 (> represents the same meaning as described above), or
  • R A1 and R A2 are joined together with adjacent carbon atoms to form CycH
  • CycH represents a C4-10 monocyclic or bicyclic carbocyclic ring or a 4-10 membered monocyclic or bicyclic heterocyclic ring
  • R 1C> has the same meaning as described above. .
  • R A1 and R 1C> are linked together with adjacent carbon and nitrogen atoms.
  • CycJ represents a 5- to LO-membered monocyclic or bicyclic heterocyclic ring, and RA represents the same meaning as described above.
  • R is (i) Cl-8 alkyl, (ii) C2-87 alkenyl, (iii) -NR R ⁇ (ix) —OR Z 3 , (v) —SR z3 , (vi) — COR z4 , (vii) CycP, or (viii) — NR Z1 R Z2 , -OR 23 , SR Z3 , COR z4 , -SO R Z4 , CycP and — P (O) (OR 25 ) (OR z6 ) force 1 ⁇ 5 selected
  • R A4 represents (0 hydrogen atom, (ii) Cl-8 alkyl, (iii) C2-8 alkyl, (iv) COR z4 , (v) CycP, or (vi) CycP, one NR Z1 R Z2 , One OR Z3 , one SR Z3 , one COR Z4 , one SO- COOR z3 , one CONR zl R z2 , -SO NR Z1 R Z2 and one P (O) (OR 25 ) (OR z6 )
  • R 1C> is a force representing the same meaning as above or
  • R A3 and R A4 are linked together with adjacent carbon and nitrogen atoms.
  • CycK represents a 5- to L0-membered monocyclic or bicyclic heterocyclic ring, and has the same meaning as described above.
  • n represents an integer of 1 or 2
  • other symbols have the same meanings as described above, and R J and R A4 are taken together with the adjacent nitrogen atom and sulfur atom.
  • CycM represents a 5- to 10-membered monocyclic or bicyclic heterocyclic ring, and the other symbols have the same meanings as described above.
  • R A3 and R 1C> are linked together with adjacent nitrogen and sulfur atoms.
  • CycN represents a 5- to 10-membered monocyclic or bicyclic heterocyclic ring, and the other symbols have the same meanings as described above.
  • CycA each independently, further CycA, CycB, CycC, CycD, CycE, CycF, CycH, CycJ, CycK, CycL, CycM, CycN and CycP is 1-5 R 27 each, independent Can be replaced by
  • R 27 is, (1) C1-8 alkyl, (2) a halogen atom, (3) - NRUR 12, (4) -OR 13, (5) - SR 1 3, (6) CycG, (7) nitro, (8) Shear (9) Oxo, (10) — COR 14 , (11) — SOR 14 , (12) — P
  • a halogen atom (ii) —NRUR 12 , (iii) —OR 13 , (iv) —SR 13 , (v) CycG, (vi) -toro, (vii) shear (viii) —COR ”, (ix) -SO R ", (x) -P (O) (OR 15 ) (OR 15 ), (xi)
  • R 11 and R 12 are each independently a hydrogen atom, Cl-4 alkyl, Cl-4 alkoxy, —C (0) 0— (Cl-4 alkyl), CycG, or CycG group.
  • R 13 represents a hydrogen atom, Cl-4 alkyl, trifluoromethyl, CycG, or Cl-4 alkyl substituted by a CycG group;
  • Multiple CycGs are each independently a 4-10 membered monocyclic or bicyclic carbocycle, or 1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1-2 5 to containing a sulfur atom of the formula: represents a monocyclic or bicyclic heterocyclic ring of LO members,
  • R 14 is, Cl ⁇ 8 alkyl, CycG, - NR 1L R 12 , -OR 13, - SR 13 or CycG,, - NRHR 12, -OR 13 or - represent Cl ⁇ 8 alkyl substituted by SR 13,
  • a plurality of R 15 each independently represent a hydrogen atom or Cl-8 alkyl.
  • CycQ is a C3-10 saturated or partially unsaturated monocyclic carbocyclic ring or one- NR Q — (wherein, R Q is Cl-8 alkyl, C2-8 acyl, SO ⁇ (Cl-8 alkyl), benzoyl, benzenesulfol, or toluenesulfo-
  • Represents ), Represents a 5- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring containing one oxygen atom and Z or one optionally oxidizable sulfur atom. ) May form a spiro bond.
  • the compound represented by the general formula (W) is (1) N— ⁇ 3— [(2Z) —2- (3-methyl-1,3-thiazolidine-1-ylidene) hydrazino] 2,3 dioxo-1 1 Tetrahydro 2H pyran-4-ylpropyl ⁇ cycloheptanecarboxamide, (2) N-[(lS) -3- ⁇ (2Z) -2-[(4R) -3,4 dimethyl-1,3 thiazolidine-1-ylidene] hydrazino ⁇ 2,3-Dioxo 1 (tetrahydro 2H pyran 1-4inole) propinole] cycloheptane power Ruboxamide, (3) N— ⁇ (IS) -1-cyclohexyl 3 -— [(2,5 dioxo-1 1-pyrrolidinyl ) Amino] 2,3 dioxopropyl ⁇ cycloheptanecarboxamide, (4) N-((IS)
  • prostaglandin receptor agonists prostaglandin receptor antagonists, vitamin D and its derivatives, calcium preparations, vitamin K and its derivatives, calcitonin preparations, strontium preparations, estrogen receptor modulators, anti-TNFi Antibody, anti-IL-6 antibody, HMG-CoA reductase inhibitor, female hormone preparation, anti-inflammatory drug, PTHrP, bone morphogenetic protein preparation, androgen receptor modulator, steroid drug, caspase 1 inhibitor, pharmaside X receptor Agonist, progesterone agonist, anti-RANKL antibody, meta-oral protease inhibitor, protein steroid preparation, calcium-sensing receptor antagonist, and glycogen synthase kinase inhibitor ] Bone mineral density increasing agent,
  • the bone metabolic disease is osteoporosis, fracture, arthritis, rheumatoid arthritis, osteoarthritis, high-strength lucidemia, bone metastasis of carcinoma, osteosarcoma, periodontal disease, and Z or bone page et al disease
  • the cathepsin K inhibitor is a compound represented by the general formula (W) described in the above item [3], a salt thereof, an N-oxide, a solvate or a prodrug thereof, and the PTHs are human ⁇ (1 -34) is a bone mineral density increasing agent according to [1],
  • Cathepsin K inhibitor is N— ⁇ 3 -— ((2Z) —2 -— (3-methyl-1,3-thiazolidine-2-ylidene) hydrazino] 2,3 dioxo-1-tetrahydro-2Hpyran-4-ylpropyl ⁇ cycloheptanecarboxamide or N— [(IS)-3- ⁇ (2Z)-2- [(4R)-3,4 dimethyl-1,3 thiazolidine-12-ylidene] hydrazino ⁇ 2,3 dioxo — 1 (tetrahydro 2H pyran 4 yl ) Propyl] cycloheptanecarboxamide;
  • the present invention relates to a bone density increasing agent comprising a combination of a cathepsin K inhibitor and PTHs, wherein the potent bone density increasing agent is osteoporosis, fracture, arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia. It is useful for treating and preventing or preventing bone metabolic diseases such as bone disease, carcinoma bone metastasis, osteosarcoma, periodontal disease and Z or bone Paget's disease.
  • the cathepsin K inhibitor used in the present invention is not particularly limited as long as it is a generally known compound.
  • the ligated products described in WO 01/40204, WO 01/44214, WO 01/55118, WO 01/55123, WO 02/96892, and WO 03/91202 are preferably used.
  • the cathepsin K inhibitor used particularly preferably is
  • a compound described in WO03 / 091202 that is, a compound represented by the above general formula (W), a salt, an N-oxide form, a solvate or a prodrug thereof.
  • the salt of the compound represented by the general formula (W) is a pharmaceutically acceptable salt, Low and water-soluble ones are preferred. Suitable salts include, for example, salts of alkali metals (potassium, sodium, lithium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), and ammonium salts (tetramethylammonium salts, tetrabutylammonium salts).
  • organic amines triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) methylamine, lysine, arginine, N-methyl D glucamine, etc.
  • acid adduct salts [inorganic acid salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic acid salts (acetic acid Salt, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, quen Acid salt, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, dalconate, etc.).
  • the N-hydroxylated compound of the compound represented by the general formula (W) includes those in which the nitrogen atom of the compound represented by the general formula (W) is oxidized. Further, the N-year-old oxide form of the compound of the present invention may further be the above-mentioned alkali (earth) metal salt, ammonium salt, organic amine salt, or acid addition salt.
  • Examples of the solvate of the compound represented by the general formula (W) include water and alcohol-based solvents.
  • the solvate is preferably non-toxic and water-soluble.
  • the solvate of the compound represented by the general formula (W) includes an alkali (earth) metal salt, an ammonium salt, an organic amine salt, and an acid-containing salt of the compound represented by the general formula (W). Also included are solvates such as salt and nitroxide form.
  • the compound represented by the general formula (W) can be converted into the above-mentioned salt, the above-mentioned N-oxide form, and the above-mentioned solvate by a known method.
  • the prodrug of the compound represented by the general formula (W) refers to a compound that is converted into a compound represented by the general formula (W) by a reaction with an enzyme, gastric acid, or the like in a living body.
  • a prodrug of the compound represented by the general formula (W) for example, when the compound represented by the general formula (W) has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated (for example, ,
  • the amino group of the compound represented by the general formula (W) may be eicosanoylated, alanylated, acetylaminocarbylated, or (5-methyl 2-oxo-1,3 dioxolene 4-yl ) Methoxycarbylation, tetrahydrofuration, pyrrolidylmethylation, bivaloyloxymethylation, acetooxymethylation, tert-butylated compound, etc.); when the compound represented by formula (W)
  • prodrug of the compound represented by the general formula (W) may be either a hydrate or a non-hydrate.
  • prodrugs of the compound represented by the general formula (W) can be obtained under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, “Molecular Design,” pp. 163-198.
  • the compound may be changed to the compound represented by the general formula (W).
  • the compound represented by the general formula (W) may be labeled with an isotope (eg, 3 H, “C, 35 S, 1251, etc.) or the like.
  • any of the compounds described in WO03 / 091202 is preferable, but more preferably, for example, the compound represented by the general formula (W-1)
  • R S and R T each independently represent a hydrogen atom or C 14 alkyl such as methyl or ethyl
  • W-2 a compound represented by the general formula (W-2)
  • R 11 represents a hydrogen atom or a methyl group
  • [0092] indicates that it is bonded to the other side of the paper ( ⁇ position). ), Salts thereof, pentoxides, solvates or prodrugs thereof.
  • (9) (N — ((1S) —3 — ⁇ (2Z) —2 — [(4S) —3,4 dimethyl-1,3,3 thiazolidine-1 2) which is an enantiomer of the compound (5) —Ilidene] hydrazino ⁇ 2,3 dioxo-1-tetrahydro2H-pyran-4-ylpropyl) cycloheptanecarboxamide) can also be suitably used.
  • the compounds (1) to (8) are produced according to the method described in WO03 / 091202. Can.
  • the compound (9) can be produced by recrystallizing the compound (8) from isopropylamine and ethyl acetate. Specifically, it can be produced by the method described in Example 1 below.
  • the dose of the compound represented by the general formula (W) used as a cathepsin K inhibitor varies depending on age, sex, body weight, symptoms, race, and the like. It depends on the route of administration, the condition of the patient's kidneys and liver, and the types of compounds and salts used. Those skilled in the art can easily prescribe the dosage required to suppress the progression of the symptoms or ameliorate and treat the disease.
  • oral administration intravenous administration, subcutaneous administration, local injection administration into a joint cavity, transdermal administration, and the like are preferable.
  • the administration interval of the cathepsin K inhibitor is, for example, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 1 week It can be administered intermittently at intervals of about 2 weeks, about January, about February, about March, about April, about June, about 1 year, etc. If taken daily, once a day! 4 times a day.
  • the compound represented by the general formula (W) can be used as a pharmaceutical composition in various dosage forms according to a method known per se, for example, the method described in WO03 / 091202.
  • the cathepsin K inhibitor can be administered as a solid preparation for oral administration and includes, for example, tablets, pills, powders, granules, capsules and the like.
  • Capsules include hard capsules and soft capsules.
  • one or more active substances are used as they are, or excipients (ratatose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders ( Hydroxypropylcellulose, polypyrrolidone, magnesium aluminate metasilicate, etc.), disintegrant (calcium glycolate, etc.), lubricant (magnesium stearate, etc.), stabilizer, solubilizer (glutamic acid, aspartic acid, etc.) It is mixed with E.g.
  • a coating agent sucrose, gelatin, hydroxypropinolecellulose, hydroxypropinolemethinolecellulose phthalate, etc.
  • a coating agent sucrose, gelatin, hydroxypropinolecellulose, hydroxypropinolemethinolecellulose phthalate, etc.
  • More gelatin Capsules of such resorbable materials are also included.
  • Liquid preparations for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
  • one or more active substances are dissolved, suspended or emulsified in a commonly used diluent (eg, purified water, ethanol or a mixture thereof).
  • the liquid preparation may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffer and the like.
  • a potent dosage form contains from about 1 mg to about 1,000 mg of the cathepsin K inhibitor. More preferably, from about 5 mg to about 300 mg.
  • the PTHs of the present invention include PTH and PTH derivatives.
  • PTH refers to parathyroid hormone (parathyroid hormone), and preferably includes natural PTH, recombinant PTH produced by genetic engineering techniques, and chemically synthesized PTH.
  • examples include human PTH consisting of 84 amino acid residues (human ⁇ (1-84)), especially recombinant human TH (1-84) produced by genetic engineering techniques.
  • a PTH derivative is, for example, a partial peptide of PTH as described above, PTH itself or a partial amino acid of the partial peptide substituted with another amino acid, or a partial amino acid of PTH itself or a partial peptide thereof.
  • ⁇ (1-34) is human PTH consisting of 34 amino acid residues from the N-terminal to the 34th amino acid of PTH (human ⁇ ⁇ (1-34), human ⁇ (1-34) amide, etc.), especially genes Recombinant human 1- (1-34) manufactured by engineering techniques (eg, CHS13340 developed as a nasal preparation) can be mentioned.
  • the PTHs may be used alone or in combination of two or more.
  • Preferred examples of amino acid substitution include substitution of a constituent amino acid at position 8 with leucine-norleucine, substitution of a constituent amino acid at position 18 with leucine or norleucine, and substitution of a constituent amino acid at position 34 with tyrosine. And the like.
  • the purity of the PTHs used in the present invention does not necessarily have to be 100%.
  • the PTHs may be substantially pure.
  • substantially pure refers to one that has been purified so as to show at least a single peak by HPLC, and is preferably single using a combination of techniques such as Sarako, SDS-PAGE, and capillary electrophoresis. Means that it was confirmed.
  • PTHs can be obtained by the method described in JP-A-6-87897, or by the method described in JP-A-4-505259 and J. Biol. Chem., 265, 17854 (1990), or Can be produced and confirmed by using the improved method described above.
  • the administration method of PTHs is preferably parenteral administration, more preferably intravenous administration, subcutaneous administration, local injection administration into joint cavity, etc., transdermal administration, transnasal administration, and more preferably subcutaneous administration. Injection and nasal administration.
  • PTHs are preferably administered intermittently. For example, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 1 week, about 2 weeks, about January, It can be administered intermittently at intervals of about February, about March, about April, about June, about 1 year, etc.
  • the dosage of the PTHs used in the present invention varies depending on the indication disease, disease state, severity, disease state, administration route, kidney and liver condition of the patient, types of compounds and salts used, and the like. Those skilled in the art can easily prescribe the dose required to suppress the progress of symptoms or treat the disease.
  • the dose is preferably about 1 ⁇ g to about 1,000 g per kg of body weight, more preferably about 5 g to about 200 g per kg of body weight.
  • additives used in the pharmaceutical composition used in the present invention commonly used excipients, binders, lubricants, stabilizers and the like are appropriately selected and used.
  • binders commonly used excipients, binders, lubricants, stabilizers and the like are appropriately selected and used.
  • the active substance is used after being dissolved, suspended or emulsified in a solvent.
  • the solvent for example, distilled water for injection, physiological saline, vegetable oil, alcohols such as propylene glycol, polyethylene glycol, and ethanol, and a combination thereof are used.
  • this injection comprises a stabilizer (eg, sodium citrate, sodium edetate, etc.), a solubilizing agent (eg, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.) ), Suspending agents (eg, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalcodium chloride, benzethonium chloride, glyceryl monostearate, polyoxyethylene hydrogenated castor oil, polysorbate, etc.)
  • Surfactants eg, polyhydric alcohols such as glycerin and macrogol, saccharides such as sorbitol, mannitol and sucrose, celluloses such as methylcellulose, carboxymethylcellulose and hydroxypropylmethylcellulose, polybutyl alcohol, polybutylpyrrolidone and carboxyl Parents such as sibi-nore polymer, sodium carboxymethyl cellulose, methinores
  • Water-soluble polymers chondroitin sulfate, etc.
  • emulsifiers eg, glycerin ester, savon (enjusaponin, quilla extract, soybean saponin, etc.)
  • sucrose fatty acid esters eg, sucrose ester, etc.
  • lecithin eg, , Plant lecithin, egg yolk lecithin, etc.
  • soothing agents eg, benzyl alcohol, chlorobutanol, propylene glycol, aminoethyl benzoate, lidocaine, etc.
  • buffers eg, phosphates (eg, hydrogen phosphate) Sodium, sodium dihydrogen phosphate, etc.
  • boric acid, borax acetate (eg, sodium acetate, etc.)
  • carbonate eg, sodium carbonate, calcium carbonate, potassium carbonate, etc.
  • citric acid L-glutamic acid Sodium, etc.
  • pH adjusters e
  • a sterile solid preparation for example, a lyophilized product is produced, and sterilized or sterilized with distilled water for injection before use. Alternatively, it can be used by dissolving it in another solvent.
  • the dosage form of the cathepsin K inhibitor and Z or PTHs used in the present invention may be, for example, encapsulated in microcapsules, in addition to oral preparations and injections produced by ordinary preparation methods.
  • a dosage form which is expected to have a local effect and a delayed action, such as being contained in a gel sheet is also possible.
  • pharmaceutically acceptable auxiliary components can be added.
  • preparations modified with polyethylene glycol or the like for the purpose of increasing the blood half-life can be used.
  • it is a non-invasive preparation.
  • auxiliary component examples include a base, a stabilizer, a preservative, a preservative, an emulsifier, a coloring agent, a fragrance, a soothing agent, an excipient, a binder, a thickener, and a buffer.
  • Specific examples include calcium carbonate, lactose, sucrose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, cocoa butter, distilled water for injection, aqueous sodium chloride, Ringer's solution, and glucose. Solution, human serum albumin and the like.
  • auxiliary component for example, a list of pharmaceutical excipients (Tokyo Pharmaceutical Manufacturers Association Medical Law Regulation Committee and Osaka Pharmaceutical Association Medical Law Research Committee member)
  • the supplementary component may be appropriately selected and used as described in (1) issued by the Association.
  • the amount of the auxiliary component to be used may be appropriately selected according to the dosage form and the like within a pharmaceutically acceptable range.
  • the method of administering the PTHs used in the present invention may be either local administration or systemic administration. Particularly, when only a specific bone is targeted, the local administration method is superior. For local administration, intermittent local administration is desirable.
  • the PTHs used in the present invention can also be absorbed as a patch.
  • PTHs used in the present invention can also be administered systemically since administration can be performed without invasion if the administration method is devised.
  • Preferable examples of the systemic administration method include whole body administration by subcutaneous administration, intravenous administration, nasal administration (intranasal administration), pulmonary administration and the like.
  • cathepsin K Administer the inhibitor alone for a certain period of time (for example, about 1 week, about January, about February, about March, about June, about 1 year, etc.) and then co-administer with PTH It is also preferable to administer PTHs alone for a certain period of time, followed by co-administration with a cathepsin K inhibitor. It is also preferable to administer the cathepsin K inhibitor and the PTHs at the same time.
  • drugs commonly used for the treatment and / or prevention of bone metabolic disorders such as calcium preparations (eg calcium lactate, precipitated calcium carbonate, etc.), estrogens Receptor modulators (eg, toremifene taenoate, tamoxifen taenoate, raloxifene hydrochloride, lasofoxifene tartrate, apeledoxifene acetate, PSK-3471 etc.), androgen receptor modulators, calcitonin preparations (eg, salmon calcitonin (STH -32, SMC20-51), tricalcitonin (MCI-536), Secarciferol, Elcatonin, TJN-135, etc.) a Calciton-gene-related peptide preparation, Ibriflavon preparation (for example, Ibriflavon etc.) ), Protein steroid preparations (Nandrolone decanoate, Nandrolone
  • An anti-RANKL (receptor activator of NF-kappa B ligand) antibody eg, AMG162); PTHrP (parathyroid hormone-related protein) (eg, RS-66271, hPTHrP etc.); BMP (bone morphogenetic protein) (eg, YM484 (BMP-2, etc.), prostaglandin receptor agonists (eg, EP agonists (eg, ONO-4819 etc.), EP agonists (eg, ONO-8815 etc.), Nitrofu
  • CaR calcium sensing receptor
  • GSK glycosyl kinase inhibitor
  • vitamin D eg, vitamin D (ergocalciferol)
  • Vitamin D cholecalcifrol
  • its derivatives for example,
  • vitamin K for example, vitamin K (phytonadione), vitamin K (menate
  • strontium preparations for example, strontium lanerate
  • HMG-CoA reductase inhibitors for example, pravastatin, simpastatin, pitavastatin, oral pastatin, rospastatin, atorvastatin, flupastatin
  • Serinostatin etc.
  • steroids eg, KB-889 (OD14, tibolone), Hybros (TZP-4238 ) Etc.
  • caspase 1 inhibitors e.g., pralnakasan, nitroflubiprofen, etc.
  • prostaglandin receptor antagonists e.g., pharmacokines X receptor agonists (e.g.,
  • SR-45023A progesterone agonists
  • anti-TNF- ⁇ antibodies eg, infliximab, etanercept
  • anti-IL-6 antibodies eg, MRA
  • female hormone preparations anti-inflammatory drugs
  • Meta-oral protease inhibitors for example, minocycline hydrochloride and the like.
  • the compounds used in the present invention have very low toxicity and are sufficiently safe for use as pharmaceuticals.
  • cathepsin I inhibitors and Class I can increase bone density more effectively than the use of Class I alone.
  • Combination is effective for osteoporosis, fractures, arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia, bone metastasis of carcinoma, osteosarcoma, periodontal disease, and bone metabolic diseases such as ⁇ or bone Paget's disease.
  • Useful for prevention and / or treatment for example, oral administration of a cathepsin ⁇ inhibitor and parenteral administration of ⁇ (subcutaneous injection, nasal administration, etc.) can effectively increase the bone density of patients with bone metabolic diseases such as osteoporosis. be able to.
  • FIG. 1 shows the bone mineral density of the left tibia (4 mm from the epiphysis) at the time of mid-term autopsy in Experiment 1 (administration schedule 1).
  • FIG. 2 shows the concentration of osteocalcin in serum, which is a bone formation marker at the time of an intermediate autopsy in Experiment 1 (administration schedule 1).
  • FIG. 3 shows the bone density of the left tibia (4 mm from the epiphysis) after 83 days in Experiment 1 (administration schedule 1).
  • FIG. 4 shows bone metabolism markers (urine CTX concentration, serum osteocalcin concentration) after 83 days in Experiment 1 (administration schedule 1).
  • FIG. 5 shows the tibia bone density (4 mm from the epiphysis) 83 days after experiment 2 (administration schedule 2).
  • FIG. 6 shows bone metabolism markers (urine CTX concentration, serum osteocalcin concentration) after 83 days in Experiment 2 (administration schedule 2).
  • the solvent in kakkoko indicated by the chromatographic separation or TLC indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
  • the solvent in kakkou indicates the solvent used for the measurement.
  • the name of the compound used in the present specification is generally a computer program for naming according to IUPAC rules, ACD / Name (registered trademark, manufactured by Advanced Chemistry Development Inc.) or ACD / Name is a name using a batch (registered trademark, manufactured by Advanced Chemistry Development In) or according to the IUPAC nomenclature.
  • the compound (I) used as a cathepsin K inhibitor was prepared in Example 8 (WO03 / 91202).
  • Alendronate sodium hydrate (hereinafter sometimes abbreviated as ALN) used as bisphosphonate (BP) was obtained from LKT Laboratory.
  • PTHs include human ⁇ (1-34) amide, a partial peptide of PTH (APC
  • Compound (I) solution Compound (I) was dissolved in a 0.5% aqueous solution of methylcellulose (MC) to prepare a 0.6 mg / mL solution.
  • ALN solution ALN is dissolved in 0.01 mol / L aqueous sodium hydroxide solution to 5.6 mg / mL. (around pH 7) and further diluted 28-fold with a 0.5% MC aqueous solution to obtain a 0.2 mg / mL solution.
  • ⁇ (1-34) solution ⁇ (1-34) is dissolved in 0.1% ⁇ serum albumin (BSA) -containing physiological saline (10 ml) to make a solution of 84 g / mL. It was diluted to a working concentration with a physiological saline solution containing% BSA (2 / zg / mL or less.
  • BSA serum albumin
  • Compound (I) used as a cathepsin K inhibitor was orally administered twice daily at a dose of 3 mg / kg, and ALN used as BP was once daily at a dose of 1 mg / kg. It was administered orally. After 55 days of OVX force, necropsy was performed in the necropsy group, bone resorption inhibitor was orally administered to the compound-administered group, and administration medium (physiological saline solution containing 0.1% BSA) was administered subcutaneously instead of PTH or PTH .
  • ALN was administered as a bone resorption inhibitor
  • ALN was orally administered the first time
  • the administration medium (0.5% MC aqueous solution) was orally administered the second time. The interval between the first and second dose was 5 to 7 hours.
  • PTH was administered subcutaneously from the back three times a week at a dose of 10 ⁇ g / kg from the 57th day after OVX.
  • Drug administration was performed according to the groupings in Table 1 below.
  • the tibial BMD bone density
  • lumbar vertebra BMD lumbar vertebral bone density
  • urinary collagen C-terminal telopeptide (CTX) concentration and blood osteocalcin (OC) concentration were measured 83 days later.
  • a bone resorption inhibitor (Compound (I) (3 mg / kg, orally administered twice a day as a cathepsin ⁇ inhibitor) and BP as ALN (1 mg / kg, 1 Oral administration once a day)) and PTH (1-34) (3 ⁇ g / kg, subcutaneously three times a day) were administered for 83 days.
  • the administration vehicle physiological saline solution containing 0.1% BSA
  • ALN was administered orally the first time
  • the administration medium (0.5% MC aqueous solution) was orally administered the second time. The interval between the first and second dose was 5-7 hours.
  • the CTX concentration was measured using a rat CTX measurement kit (RatLaps ELISA; nordicbiosdence). The absorbance was measured using a microplate reader (SPECTRA MAX 250, Nippon Molecular Devices Co., Ltd.). The measured value of urinary CTX concentration (ng / mL) was expressed by the value (ng / mg CRE) divided by the urinary creatinine concentration (mg / mL) measured for the same individual.
  • the OC concentration in the serum was measured using an OC measurement kit (BIOTRAK, Osteocalcin, rat ELISA system) using the collected serum at the autopsy day 55 days after the administration.
  • the t-test (EXSAS (version 6.1), Arm) was used to compare the sham surgery group with the control group, and the Tukey test (EXSAS (version 6.1), arm) was used to compare the efficacy of the test compounds. A difference of less than 5% was defined as a significant difference.
  • PTH, compound (I) and ALN each independently showed a decrease in tibia bone density by OVX. Improved reduction.
  • the combined administration group of PTH and compound (I) showed a significant effect on the administration of PTH alone.
  • Compound (I) showed an additive effect on tibial bone density when used in combination with PTH.
  • Combined use of ALN and PTH showed no effect.
  • FIG. 4 shows that Compound (I) showed an inhibitory effect on urinary CTX concentration, which is one of the bone resorption markers, in both the single administration group and the combined use group with PTH.
  • the urinary CTX inhibitory effect was weak in both groups.
  • Bone resorption inhibitor and PTH were administered in combination for a long time.
  • Cathepsin K inhibitors did not inhibit bone formation and selectively inhibited bone resorption, whereas experimental findings showed that BP inhibited both bone resorption and bone formation. Therefore, it became clear that the cathepsin K inhibitor was excellent in the combined effect with PTH.
  • BP is not very effective in combination with PTHs, but the present inventors found that the same bone resorption inhibitor, catebucin K inhibitor, was superior in combination with PTHs compared to BP. Is found.
  • Formulation Example 1 1 report of a formulation containing 10 mg of cathepsin K ⁇ .
  • Formulation Example 2 Report of a formulation containing 50 mg of PTH (134)
  • the solution was sterilized by a conventional method, and 5 ml of the solution was filled into vials to obtain 100 vials of a liquid containing 50 mg of the active ingredient in one vial.
  • bone density can be increased more effectively than using PTHs alone.
  • a preventive and / or therapeutic agent for bone metabolic diseases such as fractures, arthritis, rheumatoid arthritis, osteoarthritis, hypercalcemia, bone metastasis of carcinoma, osteosarcoma, periodontal disease and Z or bone page et al disease Useful.

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Abstract

[PROBLEMES] Fournir un agent densifiant les os caractérisé en ce qu'il utilise un inhibiteur de cathepsine K en association avec une PTH. [MOYENS POUR RESOUDRE LES PROBLEMES] Il est fourni un agent densifiant les os caractérisé en ce qu'il utilise un inhibiteur de cathepsine K servant de médicament pour l'inhibition de la résorption osseuse en association avec une PTH servant de médicament pour l'accélération de l'ostéogenèse. Cet agent densifiant les os est utile pour le traitement de l'ostéoporose, d'une fracture osseuse, de l'arthrite, de l'arthro-rhumatisme, de l'arthrose, de l'hypercalcémie, d'une métastase osseuse d'un carcinome, d'une maladie parodontale, de la maladie de Paget des os et d'autres maladies métaboliques des os. Par exemple, comme inhibiteur de cathepsine K, on peut mentionner un composé de formule (W) et un sel de celui-ci, etc.
PCT/JP2005/007767 2004-04-26 2005-04-25 Agent densifiant les os caracterise en ce qu'il utilise un inhibiteur de cathepsine k avec une pth WO2005102381A1 (fr)

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US11/587,557 US7632813B2 (en) 2004-04-26 2005-04-25 Bone densifying agent characterized by use of cathepsin K inhibitor with PTH
JP2006512615A JPWO2005102381A1 (ja) 2004-04-26 2005-04-25 カテプシンｋ阻害薬およびｐｔｈ類を併用することを特徴とする骨密度増加剤
EP05734608A EP1741441A4 (fr) 2004-04-26 2005-04-25 Agent densifiant les os caracterise en ce qu'il utilise un inhibiteur de cathepsine k avec une pth

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JPWO2020027200A1 (ja) * 2018-08-01 2021-08-19 小野薬品工業株式会社 軟骨関連疾患治療剤
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US7632813B2 (en) 2009-12-15
US20070238769A1 (en) 2007-10-11
JPWO2005102381A1 (ja) 2008-03-06
EP1741441A1 (fr) 2007-01-10
EP1741441A4 (fr) 2010-03-03

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